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Inoki, Isao ; 居軒, 功
概要:
取得学位 : 博士（医学）, 学位授与番号 : 医博乙第1600号, 学位授与年月日 : 平成16年11月17日, 学位授与大学 : 金沢大学
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Wang, Fei ; Okamoto, Yasuo ; Inoki, Isao ; Yoshioka, Kazuaki ; Du, Wa ; Qi, Xun ; Takuwa, Noriko ; Gonda, Koichi ; Yamamoto, Yasuhiko ; Ohkawa, Ryunosuke ; Nishiuchi, Takumi ; Sugimoto, Naotoshi ; Yatomi, Yutaka ; Mitsumori, Kunitoshi ; Asano, Masahide ; Kinoshita, Makoto ; Takuwa, Yoh
概要:
金沢大学医薬保健研究域医学系<br />Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that has pleiotropic effects in
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a variety of cell types including ECs, SMCs, and macrophages, all of which are central to the development of atherosclerosis. It may therefore exert stimulatory and inhibitory effects on atherosclerosis. Here, we investigated the role of the S1P receptor S1PR2 in atherosclerosis by analyzing S1pr2–/– mice with an Apoe–/– background. S1PR2 was expressed in macrophages, ECs, and SMCs in atherosclerotic aortas. In S1pr2–/–Apoe–/– mice fed a high-cholesterol diet for 4 months, the area of the atherosclerotic plaque was markedly decreased, with reduced macrophage density, increased SMC density, increased eNOS phosphorylation, and downregulation of proinflammatory cytokines compared with S1pr2+/+Apoe–/– mice. Bone marrow chimera experiments indicated a major role for macrophage S1PR2 in atherogenesis. S1pr2–/–Apoe–/– macrophages showed diminished Rho/Rho kinase/NF-κB (ROCK/NF-κB) activity. Consequently, they also displayed reduced cytokine expression, reduced oxidized LDL uptake, and stimulated cholesterol efflux associated with decreased scavenger receptor expression and increased cholesterol efflux transporter expression. S1pr2–/–Apoe–/– ECs also showed reduced ROCK and NF-κB activities, with decreased MCP-1 expression and elevated eNOS phosphorylation. Pharmacologic S1PR2 blockade in S1pr2+/+Apoe–/– mice diminished the atherosclerotic plaque area in aortas and modified LDL accumulation in macrophages. We conclude therefore that S1PR2 plays a critical role in atherogenesis and may serve as a novel therapeutic target for atherosclerosis.
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論文
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Konoshita, Tadashi ; Makino, Yasukazu ; Kimura, Tomoko ; Fujii, Miki ; Morikawa, Norihiro ; Wakahara, Shigeyuki ; Arakawa, Kenichiro ; Inoki, Isao ; Nakamura, Hiroyuki ; Miyamori, Isamu
概要:
Background: At the intervention for cardiovascular disease (CVD), albuminuria is a new pivotal target. Calcium channel b
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locker (CCB) is one of the most expected agents. Currently CCBs have been classified by delivery system, half-life and channel types. We tested anti-albuminuric effect among 4 types of CCBs. Methods: Subjects were 50 hypertensives (SBP/DBP 164.7 ± 17.1/92.3 ± 12.2 mm Hg, s-Cr 0.81 ± 0.37 mg/dl, urinary albumin excretion (UAE) 69.4 (33.5-142.6) mg/gCr). Four CCBs were administered in a crossover setting: nifedipine CR, a long biological half-life L type by controlled release; cilnidipine, an N/L type; efonidipine, a T/L type; and amlodipine, a long biological half-life L type. Results: Comparable BP reductions were obtained. UAE at endpoints ware as follows (mg/gCr,*P < 0.01): nifedipine CR 30.8 (17.3-81.1),* cilnidipine 33.9 (18.0-67.7),* efonidipine 51.0 (21.2-129.8), amlodipine 40.6 (18.7-94.7). By all agents, significant augmentations were observed in PRA, angiotensin I and angiotensin II (AngII). AngII at cilnidipine was significantly lower than that at amlodipine. PAC at cilnidipine and efonidipine was significantly lower than that at amlodipine. Nifedipine CR significantly reduced ANP concentration. Conclusions: It is revealed that only nifedipine CR and cilnidipine could reduce albuminuria statistically. Thus, it is suggested that the 2 CCBs might be favorable for organ protection in hypertensives. © 2011 Elsevier Ireland Ltd.
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